Verapamil (I) is presently in clinical use as the racemate and is used extensively for the treatment of hypertension. The opposite enantiomers of verapamil have different biological activities. The (S)-enantiomer (levoverapamil) has the majority of the calcium channel antagonist activity (DE-A-2059923) whilst the (R) -enantiomer (dextroverapamil) differs in having sodium channel and other cell-pump actions in addition to higher bioavailability, with slower clearance rate. These differences may be of clinical significance, for example, the (R) -enantiomer may be of benefit for the reversal of multidrug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46: 113); in this case hypotensive action by admixture with the (S) -enantiomer would be undesirable.
Thus there is a requirement for efficient manufacturing processes to produce single enantiomer or enantiomerically-enriched forms of the compound verapamil and analogues thereof. This is a challenging endeavour since construction of the quaternary chiral centre with high asymmetric induction is difficult. Several synthetic routes to such compounds have been published but for a variety of reasons most are unsuitable for preparation on a large scale.
For example, the synthesis of (S) -verapamil commencing from (S) -1,2-propanediol entails 11 steps, only 3 of which are used to create permanent skeletal bonds; see Theodore and Nelson, J. Org. Chem. (1987) 52: 1309. Of the shorter routes proceeding via classical resolution are processes disclosed in WO-A-9729081, which involve resolution of 4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoic acid (II; verapamilic acid). Such processes are potentially advantageous over the resolution of verapamil itself (disclosed in DE-A-3723684 and WO-A-9316035) due to better atom utilisation and lower waste levels. Literature methodology for the conversion of enantiomerically-enriched (II) to verapamil (1), and corresponding processes for analogues, invariably entails reduction of (II) to either the enantiomerically-enriched alcohol (III) or the enantiomerically-enriched aldehyde (IV).
Proceeding via alcohol (III) involves conversion to either an O-sulphonyl derivative or an alkyl halide, and subsequent amination to verapamil (I), which may require elevated temperatures (see GB 1367677), prolonged reaction times (see Theodore and Nelson, as above), or the use of the hazardous solvent hexamethylphosphoramide (see U.S. Pat. No. 4,940,780). Proceeding via aldehyde (IV), an a large scale from (II), requires two operations, either reduction-oxidation via alcohol (III) or acid chloride formation, and then a Rosenmund reaction. Racemic analogues of (IV) are available without recourse to this awkward adjustment of oxidation levels, but the protocols used, for instance as described in DE-A-2631222, are not suitable for preparing enantiomerically-enriched compounds.
For the above reasons it is desirable to establish a more streamlined protocol for the conversion of enantiomerically-enriched (II) to enantiomerically-enriched verapamil (I).